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Browsing by Subject "orexin"

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  • Vartiainen, Pyry (2023)
    Orexins (hypocretins) are two neuropeptides, orexin-A (OX-A) and orexin-B (OX-B), produced by a neuron subpopulation in the mammalian hypothalamus. They are natural substrates of two G-protein-coupled receptors (GPCRs), orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R), respectively. Orexin receptors are expressed widely in the central nervous system. Orexin peptides and receptors were originally discovered in 1998 and have been extensively researched ever since. Maintaining a steady state of wakefulness has been identified as one main physiological function of orexinergic signalling, and loss of orexinergic neurons in the hypothalamus has been linked to narcolepsy. Over the past decade orexin receptor antagonists have been developed for treatment of insomnia – suvorexant as the first one, approved for clinical use in 2014. Orexin receptor agonists remain under development for treatment of narcolepsy as one potential therapeutical indication, with no clinical applications yet approved. Orexin receptor activation by small-molecule agonists has proven a challenge not yet conclusively resolved. The aim of this study was to validate a novel scaffold for orexin receptor agonists from compounds identified as orexin receptor agonists in previous studies. Total of ten compounds were designed for synthesis, three of which were successfully synthesized. These three compounds exhibited very low orexinergic activity (0.06–1.36% and 2.33–5.19% response of full activation for OX1R and OX2R, respectively). After activity testing retrospective modelling of the receptor binding of the synthesized and designed compounds was implemented computationally by structure-based molecular docking to the recently discovered (2021) crystal structure of OX2R in complex with bound small-molecule agonist 3′-(N-(3-(2-(2-(2H-1,2,3-triazol-2-yl)benzamido)ethyl)phenyl)sulfamoyl)-4′-methoxy-N,N-dimethyl-[1,1′-biphenyl]-3-carboxamide. Some of the key interactions known as crucial for receptor activation, such as hydrogen bonds with glutamine Q1343.32, were found possible for some of the synthesized and designed compounds. This may in part explain the orexinergic activity, however very low, measured for the synthesized compounds. Low activity of the synthesized compounds may be a result of low binding since their binding was not tested in this study. Interactions between the synthesized compounds and OX2R predicted by molecular modelling are consistent with the low measured activity of the compounds, and alternative, more optimal chemical scaffolds for orexin receptor activation could be searched in future studies.